DESCRIPTION: The research project encompasses the systematic design, synthesis and evaluation of the safety and effectiveness of heterocyclic derivatives as orally active iron-chelating agents for the treatment of iron overload. Animal studies of a siderophore isolated from S. antibioticus, have shown the parent compound to be a very efficient iron chelator but also nephrotoxic. Dr. Bergeron and his co-workers have identified specific components of the compound that are responsible for the three major properties of interest: (1) chelation of iron, (2) nephrotoxicity, and (3) gastrointestinal absorption. This has been accomplished by designing, synthesizing and evaluating in animals a series of derivatives. At least one of the derivatives seems to be orally active and less toxic than the parent compound. Other compound may have the advantage of combining different ligands, which would act as a carrier molecular across the gastrointestinal tract. In the proposed studies, the investigators will extend their efforts to design and synthesis heterocyclic derivatives and analogues to improve the understanding of structure and activity relationships, to identify candidate compounds for further evaluation, and to define, for such compounds, their safety, efficiency, specificity, pharmacokinetics and metabolism, and effect on disposition of tissue iron in animals. The development of a safe and orally effective iron chelator would be a major advance in the treatment of iron overload.